The University of Pittsburgh Medical Center's Sexually Transmitted Infections (STI) Collaborative Research Center will conduct research with a primary focus on prevention of female reproductive tract damage due to sexually transmitted microbial agents. This program brings together a multidisciplinary group of researchers, with both clinical and basic research expertise in the field of STIs. The UPMC STI CRC will conduct research to determine methods of "prevention of female reproductive tract damage due to STIs". It will do so through a set of four interrelated and thematically linked research projects, each reflecting the particular research strengths of the Project Leaders/Principal Investigators (PI). Project 1 (Wiesenfeld, PI) will determine the importance of anti-anaerobic therapy in the treatment of women with acute PID. Project 2 (Hillier, PI) will determine the role of novel organisms in acute endometritis. Project 3 (Darville, PI) will determine the role of Toll-like receptor 2 signaling in innate and adaptive responses to Chlamydiae. Project 4 (Cherpes, PI) will determine protective T cell responses to Chlamydia trachomatis infection. Several specific areas of interest called for in the STI CRC funding opportunity announcement will be addressed by work outlined in this U19 proposal including: (1) development of treatment strategies for STIs, (2) research that provides a better understanding of vaginal ecology, including interactions between vaginal flora and STI-causing organisms, (3) research on the pathogenesis of disease caused by organisms transmitted by sexual contact and associated syndromes or conditions, and (4) research on the innate arid adaptive immune responses of the of the genital tract in relation to STIs. PROJECT 1: Importance of Anti-Anaerobic Therapy for Acute PID (Wiesenfeld, H) PROJECT 1 DESCRIPTION (provided by applicant): Pelvic inflammatory disease (PID) continues to pose great risk to the reproductive health of women worldwide, with the long-term sequelae of infertility, ectopic pregnancy, and chronic pelvic pain. The etiology of PID is generally recognized to be polymicrobial, and includes the sexually transmitted organisms Neisseria gonorrhoeae and /or Chlamydia trachomatis in approximately one-half of cases. Organisms associated with bacterial vaginosis are recovered from the upper genital tract from the majority of women with acute PID, suggesting that anaerobic organisms play an essential role in the pathogenesis of PID. Despite these findings, the Centers for Disease Control and Preventions'recommended outpatient treatment regimen does not provide effective activity against anaerobic microorganisms, leading to concerns that failure to eradicate anaerobic organisms from the upper genital tract may affect the long-term treatment goals of protecting fertility and limiting ectopic pregnancy. Our hypothesis is that an antibiotic regimen that includes anaerobic coverage will more effectively clear anaerobic microorganisms from the endometrium in women with acute PID compared to a standard antibiotic regimen lacking effective anaerobic therapy against anaerobes. Our specific aims are to 1. Compare the clearance of anaerobic organisms from the endometrium between PID treatment regimens with and without anaerobic coverage, 2. Evaluate the role of Mycoplasma genitalium in the pathogenesis of acute PID, and 3. Determine the treatment response between antibiotic treatment regimens for acute PID with and without optimal anaerobic therapy. To accomplish our goals, we will conduct a randomized phase III clinical trial in women with acute PID, comparing the only recommended treatment regimen for acute PID (ceftriaxone and doxycycline) to this same regimen with the addition of a two-week course of metronidazole. Our primary outcome is clearance of anaerobic organisms from the endometrium following treatment. As the importance of anaerobic therapy in PID remains an important yet unanswered question, the proposed study will provide critical information that will assist clinicians in the selection of the most effective antibiotic treatment regimen for women with PID.